tbuckley/cabot-search huggingface dataset:
An evaluation of cisplatin, doxorubicin, and cyclophosphamide (PAC) compared to other regimens for patients with unresectable or metastatic thymic carcinoma: A single-institution retrospective analysis.
Authors: Brice Wuthrich, Rohan Maniar, Emily Heldman, Louis Laniak, Hannah Davis, Fatemeh Ardeshir-Larijani, Aaron John Spittler, Kenneth Kesler, Patrick J. Loehrer
Journal: Journal of Clinical Oncology (2023)

e20650 Background: Thymic Epithelial Tumors (TETs) are uncommon tumors of the anterior mediastinum comprised of thymomas and Thymic Carcinomas (TC). Given the rarity of these tumors, little data exists regarding the comparative effectiveness of various combination therapies. Platinum-based treatment regimens in combination with anthracyclines (e.g., PAC), taxanes (e.g., carboplatin plus paclitaxel (CT)) or etoposide (PE) have demonstrated efficacy in TETs in the front-line setting (although current NCCN guidelines recommend only CT for the treatment previously untreated advanced TC). We sought to characterize the efficacy of these regimens for TCs in a real-world setting. Methods: We conducted a single-institution, retrospective database analysis of 164 TC patients seen at the IUSCCC from 1996 - 2020. Of those patients, 42 met the study criteria as having a de novo diagnosis of TC treated with front-line systemic chemotherapy and available outcome data. Chemotherapeutic intervention and demographic/clinical variables were evaluated in this study. Data was compiled and collected using descriptive statistics and the Kaplan Meier method for survival analysis via GraphPad Prism software. Results: Of the 42 patients identified to have sufficient data, the median age was 55.6 years (range, 21 - 82). The median follow-up for patients was 23 months. Metastatic sites of disease included the pleura (11%), lymph nodes (11%), bone (10%) and lungs (5%). Multi-site involvement accounted for 36% of cases. Squamous cell carcinoma (SCC) was found in 52.3% (n = 22) of the patients, while 26.2% (n = 11) had rare TC subtypes, including, SCC with basaloid features, SCC with neuroendocrine features, and neuroendocrine (21.4% of cases were classified as TC only). Most patients received first line treatment with PAC (n = 16), CT (n = 13) or PE (n = 9). There was no difference in progression free survival (PFS) for TC patients treated with PAC or CT (10.5 v. 7.5 months, respectively, NS). PE was associated with inferior outcomes compared to PAC (4.5 vs. 10.5 months, ***p = 0.0005) and CT (4.5 vs. 7.5 months, *p = 0.0158), respectively. A subgroup analysis of rarer histologic subtypes revealed a trend towards improved PFS for patients who received PAC compared to CT (9.5 v. 4.5 months, NS). Conclusions: The results of our study support PAC combination chemotherapy as a reasonable alternative for patients with previously untreated advanced TC. Further studies to correlate the genomic differences of common and uncommon TC subtypes will be crucial to optimize the role of conventional and targeted systemic therapies in this rare malignancy.
Clinical and molecular Characterization of NSCLCs with MET exon 14 skipping mutation coexist MET amplification.
Authors: Huimin Tian, Yuan Tan, Qin Zhang, Qianqian Duan, Tingting Sun, Chuang Qi
Journal: Journal of Clinical Oncology (2023)

e20506 Background: MET exon 14 skipping mutation (METex14) and MET amplification are the most prevalent molecular alterations associated with MET carcinogenesis in non-small cell lung cancer, with respective frequencies of 3-4% and 1-5%. Recent research indicates that patients with METex14 may also carry MET amplification, and that MET-TKI therapy has a higher response rate in this patient population. We evaluated the clinical and molecular characteristics of patients with altered or co-altered MET using NGS data of non-small cell lung cancer cases from Jiangsu Simcere diagnostic Co., ltd. Methods: During 2019-2021, samples from 33074 NSCLC patients underwent comprehensive genomic profiling (CGP) using hybrid-capture technology at the Simcere diagnostic laboratory (Nanjing, China). To detect gene mutations in tumor tissue or blood samples of patients, next-generation sequencing (NGS) was performed. MET amplification was defined as MET copy number greater than 2.25. Results: MET exon 14 skipping was found in 325 pts (0.98%), MET amplification was found in 136 pts (0.41%), and the co-alter population consisted of only 36 pts (0.11%). Receptor, Donor, D1010, Y1003, and other METex14 subtypes represented 12.0%, 36.6%, 24.6%, 0.2%, and 26.2%, respectively, of the population. Then, we divided MET-altered NSCLC patients into three groups: MET14 (carrying only METex14), AMP (carrying only MET amplification), and MET14&amp;AMP (MET14 concomitant MET amplification). The differences in age, gender, TMB copy number, and MET copy number were then compared between these groups. Patients with AMP were considerably younger than those with METex14&amp;AMP or AMP. (MET14&amp;AMP: 69.0±9.27 vs AMP: 63.5±10.6, P = 0.032; MET14: 70.0±10.9, P &lt; 0.001). The AMP group contained significantly more male patients than the MET14 group (68.0% vs. 54.5%, P = 0.019), but there were no significant differences between the remaining groups. In contrast to tissue-based TMB, the AMP group was significantly higher than the other two (AMP:17.059.5 vs MET 14: 2.945.79; P0.001; MET14&amp;AMP: 3.650.63, P = 0.005). In spite of this, there was no statistically significant difference between the AMP and MET14 &amp; AMP groups in terms of MET copy number or percentage of MET CN &gt; = 10. Conclusions: In general, AMP pts are younger and have a higher TMB than co-alteration pts; however, there is no significant difference in MET CN between AMP and co-alteration pts; whether the coexisting group is sensitive to MET-TKI is unknown, and future research should focus on the treatment of co-alteration and AMP pts.
Phase II randomized trial of first-line pembrolizumab and vorinostat in patients with metastatic NSCLC (mNSCLC): Final results.
Authors: Andreas Nicholas Saltos, Tawee Tanvetyanon, Ben C. Creelan, Michael Rahman Shafique, Scott Joseph Antonia, Eric B. Haura, Hong Zheng, Xiaoqing Yu, James Joseph Saller, Sebastian Viracacha, Ram Thapa, Theresa A. Boyle, Dung-Tsa Chen, Amer A Beg, Jhanelle Elaine Gray
Journal: Journal of Clinical Oncology (2023)

9125 Background: Histone deacetylase inhibitors enhance tumor immunogenicity through various mechanisms including induced expression of MHC and T cell chemokines. A previous phase I trial demonstrated the combination of pembrolizumab (P) with vorinostat (V) in advanced/metastatic (m)NSCLC was well tolerated with signals of activity in ICI-pretreated pts. To further investigate the combination, we conducted a first-line, phase II trial. Methods: Pts with treatment-naïve mNSCLC and tumor PD-L1 expression ≥ 1% were eligible. Pts were randomized, open-label, 1:1 to receive P 200 mg IV q3 wk as monotherapy [Arm A] vs P 200 mg IV q3 wk plus V 400 mg PO daily [Arm B]. The primary endpoint was overall response rate (ORR). Secondary endpoints included DOR, PFS and OS. Tumor biopsies were collected both pre- and on-treatment (day 15-21) for exploratory correlative analysis including gene expression and changes in the tumor microenvironment. Results: Between 7/2017 – 2/2022, 86 pts were enrolled, with 83 pts evaluable for response (40 in Arm A and 43 in Arm B). Median age was 69 (range 44 - 87), 47% female, and ECOG PS 0/1 in 9%/91%. PD-L1 TPS was ≥50% in 20/40 (50%) of pts in Arm A, and in 23/46 (50%) of pts in Arm B. The most common TRAEs in Arm A included diarrhea (15%) and fatigue (10%). 3 pts in Arm A experienced grade ≥ 3 irAEs (including 1 each of grade 3 hepatitis, pneumonitis, and rash). The most common TRAEs in Arm B included fatigue (41%), nausea (44%), diarrhea (35%) and increased creatinine (33%). 3 pts in Arm B experienced grade ≥ 3 irAE (2 grade 3 pneumonitis and 1 grade 4 myopericarditis). In Arm B, 22/45 (49%) of pts had a dose-reduction in vorinostat, most commonly due to grade 2-3 fatigue or nausea. Efficacy results by intention-to-treat are summarized in the Table below. For evaluable patients only, ORR was 44% in Arm B (19/43) and 28% in Arm A (11/40) (p=0.18). RNA-sequencing of a subset of patients showed a significant increase in interferon-γ pathway activity in both Arms. However, between the two Arms, interferon-γ pathway activity was enhanced to greater extent in Arm B, which may have contributed the higher overall response rate. Conclusions: To our knowledge, this is the first randomized trial investigating the combination of HDAC inhibition and anti-PD1 therapy in NSCLC. Although the combination arm had a numerically higher ORR compared to P monotherapy, the result did not meet the primary endpoint for significance. While there were no new safety signals with the combination therapy, reduction or interruption in V dose occurred frequently, which may have contributed to lack of survival differences between arms. Clinical trial information: NCT02638090 . [Table: see text]
Phase Ib/II study of XmAb23104 (PD1 X ICOS) and XmAb22841 (CTLA-4 X LAG3) combination in metastatic melanoma refractory to prior immune checkpoint inhibitor therapy with and without CNS disease.
Authors: Saya Jacob, Adil Daud
Journal: Journal of Clinical Oncology (2023)

TPS9595 Background: Immune checkpoint inhibitors (ICI) have greatly improved outcomes for patients by targeting programmed cell death protein 1 (PD1), cytotoxic T-lymphocyte–associated antigen 4 (CTLA4) and Lymphocyte Activation Gene-3 (LAG-3) to increase immune-mediated anti-tumor response. Despite these advances, ~50% of patients with metastatic melanoma do not respond to standard of care ICI. We strive to address this unmet clinical need through a Phase Ib/II, first-in-human, multi-center trial of two bispecific antibodies targeting four different immune checkpoints: XmAb23104 (PD1 X ICOS) and XmAb22841 (CTLA-4 X LAG3) in patients with melanoma refractory to ICI. This is the first trial of quadruple checkpoint inhibitor therapy. Furthermore, bispecific antibodies may allow simultaneous checkpoint blockade on the same cell and have been shown to heighten T cell activation in pre-clinical models. Two ongoing phase I trials of these bispecific antibodies with PD1 therapy have observed an immune related adverse event (irAE) rate of 20-24% with efficacy analysis ongoing (NCT03752398; NCT03849469). We postulate that treatment with XmAb23104 and XmAb22841 will enhance immune activation, overcome resistance, and improve disease control for patients refractory to traditional ICI. Methods: Eligible patients must have advanced/metastatic melanoma and have progressed on prior PD1/PD-L1 inhibitor or PD1/CTLA4 dual inhibition. Cutaneous, acral, mucosal and melanoma of unknown origin are allowed. Patient with CNS metastasis are allowed if these are asymptomatic and stable on MRI imaging obtained within 4 weeks of enrollment. Patients with prior unresolved irAE or irAE ≥ grade 3 are not allowed. XmAb23104 and XmAb22841 will be given on D1 and D15 of a 28-day cycle for 4 cycles, after which XmAb23104 (PD1 X ICOS) will be given alone for a total of 2 years. The phase I portion will be a dose escalation using standard 3+3 design of XmAb22841 (CTLA-4 X LAG3) with three dose levels (0.3 mg/kg, 1 mg/kg and 3 mg/kg). The dose of XmAb23104 (PD1 X ICOS) will remain at 10 mg/kg. These doses were selected based on results of prior early phase trials when these agents were combined with PD1. Once the P2RD of XmAb22841 (CTLA-4 X LAG3) is established, we will move on to dose escalation using a Simon’s 2-stage design. This portion will include two arms: Arm A consisting of 17 patients without CNS disease and Arm B consisting of 17 patients with CNS disease (total 34). Primary endpoints include dose limiting toxicities (DLT)/irAE and Objective Response Rate (ORR) at the time of best response by RECIST 1.1. Secondary endpoints include progression-free survival, overall survival, CNS response. At the time of this abstract submission, Cohort 1 of dose escalation has begun with the first few patients still within the DLT observation window. Clinical trial information: NCT05695898 .
Ceruminous adenocarcinoma: A National Cancer Database study of demographic characteristics.
Authors: Beau Hsia, Darby Keirns, Peter T. Silberstein, Xinxin Wu
Journal: Journal of Clinical Oncology (2023)

e18084 Background: Ceruminous adenocarcinoma (CA) is a rare form of malignancy that originates from the ceruminous glands located in the external auditory canal. Despite its rarity, 25% of CA patients succumb to the disease within two years of diagnosis. Radiation treatment improves the 10-year survival rate to 60%, up from 30% without radiation treatment. Due to the rarity of CA, the diagnostic trend of the disease could offer valuable insight into its epidemiology. The National Cancer Database (NCDB) database was analyzed to determine the demographic factors in patients diagnosed with CA. Methods: A retrospective cohort analysis utilizing the 2004–2020 National Cancer Database (NCDB) included patients with a histologically-confirmed diagnosis of CA (N = 37). Demographic factors (age, sex, race, Hispanic status, educational attainment, insurance status, facility type, distance from facility, and Charles/Deyo score) were analyzed by descriptive statistics and incidence trends were interpreted in regression analysis. Results: A total of 37 patients were identified in the database with a confirmed diagnosis of CA between 2004 – 2020 with a steady incidence of patients diagnosed per year (R 2 = 0.0). The average age of diagnosis was 59.7 years (SD = 16.5, range = 14 – 90 years). The top primary site was the external ear (89.2%), although primary sites on other areas of the skin did occur. Most individuals (89.2%) had Charlson/Deyo comorbidity scores of 0. The majority of the patients were Non-Hispanic White (89.1%). More patients were in the top quartile of income earners (35.5.%) compared to those in the second, third, or fourth quartiles. A higher percentage of patients were privately insured (51.4%) than those who were uninsured or insured by Medicare/Medicaid. More patients lived in metropolitan counties with a population greater than 1 million (43.2%) than in other metropolitan counties (35.1%). Fewer patients were treated in an academic/research program (40.5%) than in a non-academic program (46.0%). Patients lived an average of 43.3 miles (SD = 74.7, range = 1.8 – 370) from the treatment facility. No patients received palliative care. Conclusions: This is the first NCDB analysis on CA to the best of our knowledge and thus addresses a significant knowledge gap on the topic. The majority of CA patients tend to be non-Hispanic and White with a primary site diagnosis presenting at the external ear, similar to earlier descriptions in case reports. This is the first time the socioeconomic factors of CA patients have been described in the literature: CA patients are more likely to be in the top income quartile, live in densely-populated metropolitan areas, and be treated in a non-academic program. Further research is needed to better understand the impact of demographic and socioeconomic factors on the diagnosis of, treatments utilized against, and overall survival of patients with CA.
Patient-provider communication factors associated with mt-sDNA screening for colorectal cancer.
Authors: Shama Alam, Xuan Zhu, Gabriel Madson, Linda Squiers, Leah Helmueller, Brian Southwell, Carlye Gates, Bonny Kneedler, Paul J. Limburg, Lila J. Finney Rutten
Journal: Journal of Clinical Oncology (2023)

e22514 Background: Several colorectal cancer (CRC) screening tests, shown to reduce CRC incidence and mortality, are recommended for average-risk adults aged 45-75 years. CRC screening is underutilized in the US with access to facility-based options, such as colonoscopy, representing a barrier to screening. Stool-based tests are guideline-endorsed and offer patients a convenient and more accessible CRC screening option that can be completed at home. Provider recommendation is consistently identified as the primary factor driving patient adherence. Understanding how aspects of patient-provider communication influence CRC screening can inform interventions to improve adherence. We developed a survey, informed by behavioral theory, to identify communication factors associated with completion of mt-sDNA screening. Methods: Adults aged 45-75 years, with a US postal address, who received a valid order for mt-sDNA and whose kit was shipped between 5/21-9/21 were eligible for sampling. The survey was administered by RTI International between 3/22-6/22. Participants could complete electronic or paper surveys. We fit a multivariable logistic regression to identify patient-provider communication factors associated with mt-sDNA test completion. Results: 2,973 respondents completed the survey (response rate = 21.7%). The majority (77.3%) completed the mt-sDNA test and said they would be ‘very likely’ (76.8%) to complete Cologuard in the future. The proportion of respondents who had conversations with their healthcare provider about Cologuard, and the specific content of those conversations, was significantly different between completers and non-completers and between respondents who said they were ‘very likely’ to complete Cologuard in the future compared to respondents who were not. Results from a binary logistic regression suggested that discussions with a healthcare provider related to step-by-step instructions for completing Cologuard (OR = 1.62) and needing to have a colonoscopy follow-up (OR = 1.93), as well as feeling included ‘a great deal’ in the decision-process with respondents’ healthcare provider (compared to ‘somewhat’ or ‘not at all’) increase the odds of kit completion. Additionally, healthcare provider discussions relating to test cost (OR = 1.47) and performance (OR = 1.72), as well as feeling included ‘a great deal’ in the decision-process was positively associated with respondents indicating they were ‘very likely’ to use Cologuard in the future. Provider discussions about the cost of a follow-up colonoscopy was negatively associated with a ‘very likely’ future user (OR = 0.52). Conclusions: Healthcare providers play a key role in patient adherence to CRC screening and must be appropriately prepared and resourced to educate and to engage patients in shared decision-making about CRC screening.
Effect of testing for BRCA1/2 on outcomes in patients with ovarian cancer treated with PARPi in 1st line maintenance (1LM).
Authors: Lucio N. Gordan, Anupama Vasudevan, Sandy English, Alison Roos, Marielle Fares, Lindsay Aton, Brandon Wang, Simon Blanc
Journal: Journal of Clinical Oncology (2023)

e17576 Background: The treatment of ovarian cancer (OC) has expanded with the approval of PARPi in 1LM. Guidelines recommend that all women with OC get tested for BRCA1/2 and HRD status, given the therapeutic implication. Methods: This retrospective observational study used de-identified records from the Integra Connect PrecisionQ database enriched with information obtained by curation. Adult patients (&gt;18 yrs) with OC who had initiated treatment between 01/01/2019 and 12/31/2021 were included. Categorical variables were reported as proportions and continuous variables as median (interquartile range, IQR), as appropriate. Results: In the 1,093 patients studied, the median age was 69 yrs and 75% had high grade carcinomas. Patients were predominantly White (74%); 9% were African American. 65% were ECOG 0-1 and 8% were ECOG 2. The first line (1L) treatment included platinum (Pl) chemotherapy alone in 60% (678) and Pl + bevacizumab (bev) in 37% (401), with 86% of patients being Pl-sensitive (929/1079). Most patients (84%, 782/929) received a BRCA test, of which 415 were tested for BRCA only and 367 were BRCA/HRD. The median turnaround time was 11 days (IQR=9) for BRCA tests and 15 days (IQR=35) for HRD tests. Of 929 patients who were Pl-sensitive, 503 (54%) received 1LM and 426 (46%) did not receive 1LM. Of 503 patients who received 1LM, 86% (435) had BRCA test results and 41% (208) had HRD results before maintenance initiation. In 48 patients who received 1LM, BRCA/HRD test results were not reported before initiation of maintenance. Patients who received Pl-only induction received bev (24), niraparib (94), olaparib (O) (78), rucaparib (5), O+bev (2), or nira+bev (6) in 1LM. Patients who had Pl+bev induction received bev (134), niraparib (28), O (29), and O+bev (57), or nira+bev (18) in 1LM. The median time to discontinuation (TTD) in all patient groups regardless of BRCA/HRD testing and results, was 24 mo. (13.8-NR) with O+bev and 22 mo. (17-NR) with O alone, compared to 7.8 mo. (6.9-10.1) with bev, and 8.2 mo. with niraparib (6.7-9.9). The probability of remaining on treatment at 3 mo. for O, niraparib, or O+bev was &gt;90% compared to 80% with bev alone and remained high at 6 mo. (&gt;80% for O or O+bev). The benefit was sustained for O and O+bev-treated groups, with an 18-mo. prob. of remaining on treatment of 57% (45-67) for O and 52% (36-65) for O+bev compared to 16% (10-24) for bev. Ongoing analyses will evaluate the TTD in patient subgroups by BRCA/HRD mutation status. Conclusions: Patients who had a test result and started a PARPi in 1LM had a longer TTD compared to bev-only treated groups, underscoring the importance of genetic testing for the initiation of 1LM and outcome improvement. [Table: see text]
<i>POT1</i> germline pathogenic variants and evolving understanding of tumor spectrum: Evidence for lung cancer predisposition.
Authors: Michael Francis Walsh, Semanti Mukherjee, Ming Gao, Elise Fiala, Audrey Mauguen, Yelena Kemel, Chaitanya Bandlamudi, Miika Mehine, Maria Isabel Carlo, Yonina R. Murciano-Goroff, Joseph Vijai, Ozge Birsoy, Diana Mandelker, Michael F. Berger, David Randolph Jones, Charles M. Rudin, Marc Ladanyi, Zsofia Kinga Stadler, Kenneth Offit
Journal: Journal of Clinical Oncology (2023)

10511 Background: As a critical component of the shelterin complex, the protection of telomeres 1 protein (POT1) plays important roles in telomere length regulation and tumorigenesis. POT1 germline pathogenic/likely pathogenic variants (PVs) have been primarily linked to the development of melanoma, chronic lymphocytic leukemia, and glioma. Recent studies report POT1 PVs also predispose to other tumors such as certain sarcomas and thyroid cancer. Methods: To better understand the role of POT1 in the development of solid tumors, we explored the spectrum of POT1 germline variants in 6644 patients with POT1 sequencing performed utilizing the MSK-IMPACT assay. Results: In total, 91 POT1 germline rare variants (population frequency &lt; 0.01%) were identified in our cohort in 90 patients across 47 cancer types. We found 16 POT1 PVs including frameshift variants (p.Ile49fs, p.Gln358fs, p.Asp617fs), a nonsense variant (p.Arg363Ter), a missense variant (p.Asp224Asn), and splice site variants (c.10-2A &gt; C, c.1369+1G &gt; T). One cutaneous melanoma patient, one uveal melanoma patient, and one glioma patient were identified to have POT1 PVs. Interestingly, 8 patients with germline POT1 PVs were diagnosed with lung cancer (7 with lung adenocarcinoma and one with small cell lung cancer). Three of these 7 patients with lung adenocarcinoma had biallelic inactivation of POT1 in their tumor. The proportions of POT1 PVs in MSK lung adenocarcinoma compared to the gnomAD non-cancer control cohort were statistically significantly different (odds ratio = 16.28, 95%CI = 6.52-33.54, P = 2.87e-06). Moreover, of the 90 patients with rare germline POT1 variants, 22 had POT1 biallelic inactivation, and 9 of these 22 were diagnosed with lung adenocarcinoma. Conclusions: Taken together, our study refines the role of POT1 germline variants in solid tumors and highlights an apparent association of POT1 PVs with lung adenocarcinoma development.